The present invention relates generally to compositions and methods for treating atherosclerosis; more particularly, it relates to methods and substrate compositions for treating atherosclerosis whereby the many and varied problems associated with the disease can be arrested, substantially alleviated or even to a certain extent cured. Still more particularly, the present invention utilizes mixtures of biologically active levorotatory (L-form) amino acids to accomplish these results.
In the United States and Western Europe, cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death. One specific entity significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs. During each of the past five years, more than 550,000 deaths have occurred annually in the United States alone as a result of coronary artery disease. Additionally, more than 680,000 hospitalizations for myocardial infarction, the major complication of atherosclerosis, occur annually, and the number is steadily increasing. In recent years, more people in the United States have died as a result of atherosclerosis than of cancer, trauma and infectious diseases combined.
In 1983, the direct health care costs for the management of patients with coronary heart disease in the United States exceeded $8 billion. During the same period the total economic cost to this nation as a result of coronary heart disease as a manifestation of atherosclerosis alone was in excess of $60 billion and for 1987 is estimated to reach $96 billion. These costs do not even reflect the expense required for the management or treatment of the many and varied non-cardiac, atherosclerosis induced conditions.
Atherosclerosis is a disease characterized by the deposition of fatty substances, primarily cholesterol, and subsequent fibrosis in the inner layer (intima) of an artery, resulting in plaque deposition on the surface of, and degenerative changes in, an arterial wall. The ubiquitous arterial fatty plaque is the earliest lesion of atherosclerosis, often found even in children, and is a grossly flat, lipid-rich atheroma consisting of both macrophages (white blood cells) and some smooth muscle fibers. The fibrous plaque representative of the various forms of advanced atherosclerosis has increased intimal smooth muscle cells surrounded by a connective tissue matrix and containing variable amounts of intracellular and extracellular lipid. At the luminal surface of the artery, this plaque or lesion is usually covered by a dense fibrous cap of smooth muscle or connective tissue. Beneath the fibrous cap, the lesions are highly cellular consisting of macrophages, other leukocytes and smooth muscle cells. Deep in this cell-rich region may be areas of cholesterol crystals, necrotic debris and calcification.
If the disease is allowed to progress, it can cause narrowing and obstruction of the lumen of the artery resulting in diminished or occluded blood flow and, consequently, ischemia or infarction of the predominantly affected organ or anatomical part such as the brain, heart, intestine or extremities. The result can be significant loss of function, loss of cellular substance, emergency medical and/or surgical procedures, and significant disability or death. Alternatively, the arterial wall can be severely weakened by the infiltration of the muscular layer with the lipid (cholesterol), inflammatory white blood cells, connective tissue and calcium, resulting in soft and/or brittle areas which can become segmentally dilated (aneurysmal) and rupture or crack leading to organ, limb or even life-threatening hemorrhage.
While the basic definitive cause or causes of atherosclerosis are not fully known or understood, it has been hypothesized that this disorder is related to the plasma cholesterol and lipid levels based on empiric clinical observations of many investigators and medical practitioners. Consequently, one of the currently favored regimens for treating atherosclerosis consists of medication, dietary management, behavior modification and exercise aimed at controlling and reducing the plasma cholesterol levels.
Common medications used to lower plasma cholesterol levels include Atromid-S.RTM. (clofibrate), Choloxin.RTM. (dextrothyroxine sodium), Colestid.RTM. (colestipol hydrochloride), Lopid.RTM. (gemfibrozil), Lorelco.RTM. (probucol), Nicolar.RTM. (niacin/nicotinic acid) and Questran.RTM. (cholestyramine resin). These drugs, and the treatments in general, however, are directed only at the cause and not the result of atherosclerosis and have not been shown to be effective in reversing the plaque deposition and degenerative changes in the arterial walls. The pharmacologic agents also have many other shortcomings such as, for example, adverse side effects (hypertension, cardiac arrhythmias, gastrointestinal disturbances, headache, hypersensitivity, etc.), contraindications (heart, liver or kidney disease, pregnancy, etc.), requirement for lifelong conscientious administration, difficulty in maintaining consistent patient compliance, variable reliability and high cost.
Once the disease has progressed to the stage of significant persistent symptoms and compromised function, the next treatment step has conventionally been artery bypass grafting to repair and/or replace the damaged artery. While coronary artery bypass has become one of the more common major cardiovascular surgical procedures in the United States, surgery clearly is not the solution to the pathologic process since it has no arresting or reversing effect on the progress of the disease and only temporarily overcomes the most critically affected artery or arteries by bypassing them, if possible. Moreover, there is a significant risk of morbidity and mortality associated with surgery which many patients are reluctant to accept. Indeed, the disease may continue to progress even as the operation is being performed, and the autogenous veins or arteries used to bypass the disease impaired arteries undergo atherosclerosis changes postoperatively generally at a faster rate than the original, affected arteries. Furthermore, the conclusion reached by the Coronary-Artery Surgery Study (CASS) sponsored by the National Heart, Lung and Blood Institute (NHLBI) is that there is no overall statistical benefit in the survival rate or the rate of development of myocardial infarction between the surgically and medically treated groups of patients.
As an alternative to coronary bypass surgery, it has been suggested that certain medications and procedures may be used to treat the results of atherosclerosis and not just the cause. These treatments include chelation with ethylene diamine tetraacetic acid (EDTA) and percutaneous transluminal coronary angioplasty (PTCA). EDTA treatments, however, are still experimental, unproven and potentially as harmful as they are beneficial. PTCA treatments are invasive, of limited application and success and occasionally manifest lethal complications. Highly experimental intra-arterial laser beam plaque vaporization has limited application and requires an open operative approach to affected vessels.
It has now been surprisingly discovered that parenterally administered solutions comprising certain mixtures of biologically active amino acids are effective in both markedly reducing plasma cholesterol levels and arresting and reversing arterial plaque deposition and degenerative vascular changes associated with atherosclerosis.
Certain amino acid solutions have been parenterally administered intravenously during the past three to four decades for a variety of medical reasons. Total Parenteral Nutrition (TPN), or intravenous hyperalimentation, is now a widely accepted technique for management of nutritional and metabolic problems in patients whose absorption and assimilation of adequate or optimal nutritional substrates cannot or should not be achieved via the alimentary tract. Indeed, use of this technique, pioneered by the present inventor, has been successful in supporting normal growth and development in infants and in one child for more than fifteen years since birth.
Currently, a number of standard TPN solutions are commercially available in the United States, including those sold under the trade name TRAVOSOL.RTM. (Travenol Laboratories), FREAMINE.RTM. (McGaw Laboratories), AMINOSYN.RTM. (Abbott Laboratories) and NOVAMINE (Cutter Medical, Division of Miles Laboratories). These standard intravenous feeding solutions are designed to be nutritionally balanced, that is, they are formulated to provide all of the caloric, protein (amino acid), vitamin, mineral, water and trace element requirements of the average patient. The components of these solutions are also available in modular form, allowing the physician and pharmacist to formulate special solutions tailored to the specific needs of patients during the course of their management. Essential fatty acids and additional calories in the form of a lipid can also be administered separately intravenously as fortified emulsions of soybean or safflower oil in order to meet specific nutritional requirements. In patients with renal failure, hepatic failure or severe stress, special intravenous formulations of amino acids are also commercially available for infusion as an adjunct to the management of these conditions. For example, U.S. Pat. No. 3,832,465 describes an amino acid solution for nutritional use and U.S. Pat. No. 3,950,529 describes administration of amino acids to patients having liver disease.
No suggestion has been made, however, that parenterally administered biologically active amino acid solutions might be used to treat atherosclerosis, particularly with respect to the reversal of the detrimental complications associated with the disease.
It is, therefore, an object of the present invention to provide amino acid compositions and methods for treating atherosclerosis whereby not only the plasma cholesterol levels (contributing cause) are lowered, but also the plaque deposition and degenerative arterial changes (results) and secondary complications associated with the disease can be substantially arrested, reversed or even to a certain extent cured.
It is a further object of the present invention to provide amino acid compositions and methods for treating atherosclerosis which do not produce the many side effects of conventional drug treatments and can effectively decrease or even eliminate the need for major surgery or other interventional procedures in most atherosclerosis patients.